1. Field of the Invention
This invention relates to novel dibenzopyrans and more particularly to 1,9-dihydroxy-hexahydrodibenzopyrans having in the 3-position (1) an aryl or cycloalkyl group (W) linked to said position by an alkylene group; or (2) a methyl, aryl or cycloalkyl group linked to said position via (a) O, S, SO or SO.sub.2 groups; or (b) an alkylene group interrupted by an O, S, SO or SO.sub.2 group; or (c) an alkylene group attached to said 3-position or to said methyl, aryl or cycloalkyl groups by O, S, SO or SO.sub.2 ; to intermediates therefor and derivatives thereof; and to the use of such dibenzopyrans and derivatives thereof as analgesic, hypotensive, antisecretory and anti-anxiety agents, as immunosuppressants and tranquilizers in mammals, including man.
2. Description of the Prior Art
Despite the current availability of a number of analgesic agents, the search for new and improved agents continues, thus pointing to the lack of an agent useful for the control of broad levels of pain and accompanied by a minimum of side-effects. The most commonly used agent, aspirin, is of no practical value for the control of severe pain and is known to exhibit various undesirable side-effects. Other, more potent analgesic agents such as d-propoxyphene, codeine, and morphine, possess addictive liability. The need for improved and potent analgesic agents is, therefore, evident.
The analgesic properties of 9-nor-9.beta.-hydroxyhexahydrocannabinol and of other cannabinoid structures, such as .DELTA..sup.8 -tetrahydrocannabinol (.DELTA..sup.8 -THC) and its primary metabolite, 11-hydroxy-.DELTA..sup.8 -THC have been reported by Wilson and May, Absts, Papers, Am. Chem. Soc., 168 Meet., MEDI 11 (1974), and J. Med. Chem., 17, 475-476 (1974).
U.S. Pat. Nos. 3,507,885 and 3,636,058, issued Apr. 21, 1970 and Jan. 18, 1972, respectively, describe various 1-hydroxy-3-alkyl-6H-dibenzo-[b,d]pyrans having at the 9-position substituents such as: oxo, hydrocarbyl and hydroxy or chloro, hydrocarbylidene, and intermediates therefor.
U.S. Pat. No. 3,649,650, issued Mar. 14, 1972, discloses a series of tetrahydro-6,6,9-trialkyl-6H-dibenzo[b,d]pyran derivatives having at the 1-position an .omega.-dialkylaminoalkoxy group active as psychotherapeutic agents.
German Specification No. 2,451,934, published May 7, 1975, describes 1,9-dihydroxy-hexahydrodibenzo[b,d]pyrans and certain 1-acyl derivatives thereof having at the 3-position an alkyl or alkenyl group, as hypotensive, psychotropic, sedative and analgesic agents. The precursor hexahydro-9H-dibenzo[b,d]pyran-9-ones used in their preparation, and which are reported to have the same utility as the corresponding 9-hydroxy compounds, are described in German Specification No. 2,451,932, published May 7, 1975.
German Specification No. 2,415,697, published Oct. 17, 1974, describes 1-hydroxy-6,6,9-trimethyl-hexahydrodibenzo[b,d]pyran derivatives, and intermediates therefor, having at the 3-position an aralkyl, (substituted aralkyl) or pyridylalkyl group. They are useful as analgesic agents and as mild tranquilizers.
U.S. Pat. No. 3,856,821, issued Dec. 24, 1974, describes a series of 3-alkoxy substituted dibenzo[b,d]pyrans having antiarthritic, antiinflammatory and central nervous system activity.
A stereospecific synthesis of (-)trans-6a,7,8,10a-tetrahydro-3-pentyl-6,6,9-trimethyl-6H-dibenzo[b,d]pyr an-1-ol, more commonly known as (-)-.DELTA..sup.1 -tetrahydrocannabinol, has been reported by Razdan et al. (J. Am. Chem. Soc., 96, 5860-5, 1974). The process, a one-step synthesis, comprises the reaction of cis/trans-(+)-p-mentha-2,8-dien-1-ol with olivetol in the presence of 1% boron trifluoride etherate and anhydrous magnesium sulfate in methylene chloride at 0.degree. C. The tetrahydro compound thus produced is converted to the corresponding 9-keto hexahydro compound by the procedure of Wildes et al., J. Org. Chem., 36, 721-3 (1971). The procedure involves methylation of the 1-hydroxy-tetrahydro compound to its methyl ether and thence to the hydrogen chloride adduct by reaction with zinc chloride and HCl at 0.degree. C. in chloroform. The adduct is then dehydrohalogenated by reaction with potassium tricyclopentylcarbinolate to give the corresponding 6a,7,8,9,10,10a-hexahydro-3-pentyl-6,6-dimethyl-9-methylene-6H-dibenzo[b,d ]pyran-1-ol methyl ether. Oxidation of the 9-methylene group with potassium permanganate-periodate affords the 9-ketone. Demethylation of the methyl ether with pyridinium chloride or other acid reagent affords the alcohol.
Bergel et al., J. Chem. Soc., 286-7 (1943) investigated the replacement of the pentyl group at the 3-position of 7,8,9,10-tetrahydro-3-pentyl-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-ol by alkoxy (butoxy, pentoxy, hexoxy and octoxy) and found that it led to biological inactivity. The hexoxy derivative was reported to exhibit feeble hashish activity at 10 to 20 mg./kg. The remaining ethers showed no activity in doses up to 20 mg./kg.
In a more recent study, Loev et al., J. Med. Chem., 16, 1200-6 (1973) report a comparison of 7,8,9,10-tetrahydro-3-substituted-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-o ls in which the 3-substituent is --OCH(CH.sub.3)C.sub.5 H.sub.11 : --CH.sub.2 CH(CH.sub.3)C.sub.5 H.sub.11 or CH(CH.sub.3)C.sub.5 H.sub.11. The ether side chain containing compound was 50% less active in central nervous system activity than the corresponding compound in which the alkyl side chain is directly attached to the aromatic ring, rather than through an intervening oxygen atom; and 5 times as active as the compound in which oxygen is replaced by methylene.